Genomic analyses identify molecular subtypes of pancreatic cancer

  • Nature. 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965.
Peter Bailey  1  2 ,  David K Chang  2  3  4  5 ,  Katia Nones  1  6 ,  Amber L Johns  3 ,  Ann-Marie Patch  1  6 ,  Marie-Claude Gingras  7  8  9 ,  David K Miller  1  3 ,  Angelika N Christ  1 ,  Tim J C Bruxner  1 ,  Michael C Quinn  1  6 ,  Craig Nourse  1  2 ,  L Charles Murtaugh  10 ,  Ivon Harliwong  1 ,  Senel Idrisoglu  1 ,  Suzanne Manning  1 ,  Ehsan Nourbakhsh  1 ,  Shivangi Wani  1  6 ,  Lynn Fink  1 ,  Oliver Holmes  1  6 ,  Venessa Chin  3 ,  Matthew J Anderson  1 ,  Stephen Kazakoff  1  6 ,  Conrad Leonard  1  6 ,  Felicity Newell  1 ,  Nick Waddell  1 ,  Scott Wood  1  6 ,  Qinying Xu  1  6 ,  Peter J Wilson  1 ,  Nicole Cloonan  1  6 ,  Karin S Kassahn  1  11  12 ,  Darrin Taylor  1 ,  Kelly Quek  1 ,  Alan Robertson  1 ,  Lorena Pantano  13 ,  Laura Mincarelli  2 ,  Luis N Sanchez  2 ,  Lisa Evers  2 ,  Jianmin Wu  3 ,  Mark Pinese  3 ,  Mark J Cowley  3 ,  Marc D Jones  2  3 ,  Emily K Colvin  3 ,  Adnan M Nagrial  3 ,  Emily S Humphrey  3 ,  Lorraine A Chantrill  3  14 ,  Amanda Mawson  3 ,  Jeremy Humphris  3 ,  Angela Chou  3  15 ,  Marina Pajic  3  16 ,  Christopher J Scarlett  3  17 ,  Andreia V Pinho  3 ,  Marc Giry-Laterriere  3 ,  Ilse Rooman  3 ,  Jaswinder S Samra  18  19 ,  James G Kench  3  19  20 ,  Jessica A Lovell  3 ,  Neil D Merrett  5  21 ,  Christopher W Toon  3 ,  Krishna Epari  22 ,  Nam Q Nguyen  23 ,  Andrew Barbour  24 ,  Nikolajs Zeps  25 ,  Kim Moran-Jones  2 ,  Nigel B Jamieson  2  26  27 ,  Janet S Graham  2  28 ,  Fraser Duthie  29 ,  Karin Oien  3  29 ,  Jane Hair  30 ,  Robert Grützmann  31 ,  Anirban Maitra  32 ,  Christine A Iacobuzio-Donahue  33 ,  Christopher L Wolfgang  34  35 ,  Richard A Morgan  34 ,  Rita T Lawlor  36  37 ,  Vincenzo Corbo  36 ,  Claudio Bassi  38 ,  Borislav Rusev  36 ,  Paola Capelli  37 ,  Roberto Salvia  38 ,  Giampaolo Tortora  39 ,  Debabrata Mukhopadhyay  40 ,  Gloria M Petersen  40 ,  Australian Pancreatic Cancer Genome Initiative ,  Donna M Munzy  7  8 ,  William E Fisher  41 ,  Saadia A Karim  42 ,  James R Eshleman  34 ,  Ralph H Hruban  34 ,  Christian Pilarsky  31 ,  Jennifer P Morton  42 ,  Owen J Sansom  42  43 ,  Aldo Scarpa  36  37 ,  Elizabeth A Musgrove  2 ,  Ulla-Maja Hagbo Bailey  2 ,  Oliver Hofmann  2  13 ,  Robert L Sutherland  3 ,  David A Wheeler  7  8 ,  Anthony J Gill  3  19 ,  Richard A Gibbs  7  8 ,  John V Pearson  1  6 ,  Nicola Waddell  1  6 ,  Andrew V Biankin  2  3  4  5  27 ,  Sean M Grimmond  1  2  44
Affiliations
  • 1. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
  • 2. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
  • 3. The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.
  • 4. Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.
  • 5. South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia.
  • 6. QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
  • 7. Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 8. Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 9. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 10. Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA.
  • 11. Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia.
  • 12. School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia.
  • 13. Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
  • 14. Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia.
  • 15. Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia.
  • 16. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia.
  • 17. School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia.
  • 18. Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia.
  • 19. University of Sydney, Sydney, New South Wales 2006, Australia.
  • 20. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia.
  • 21. School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia.
  • 22. Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia.
  • 23. Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.
  • 24. Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia.
  • 25. School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia.
  • 26. Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK.
  • 27. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.
  • 28. Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK.
  • 29. Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK.
  • 30. GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK.
  • 31. Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
  • 32. Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA.
  • 33. The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 34. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
  • 35. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
  • 36. ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy.
  • 37. Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy.
  • 38. Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
  • 39. Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy.
  • 40. Mayo Clinic, Rochester, Minnesota 55905, USA.
  • 41. Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
  • 42. Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
  • 43. Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK.
  • 44. University of Melbourne, Parkville, Victoria 3010, Australia.
PMID: 26909576 DOI: 10.1038/nature16965
Abstract

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, Wnt, Notch, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of Pancreatic Cancer subtypes and identify opportunities for therapeutic development.